Methods and compositions for the prevention and treatment of inflammation, osteoarthritis, and other degenerative joint diseases

ABSTRACT

Methods and compositions for preventing and/or treating degenerative joint diseases including osteoarthritis as well as inflammation of the joints and for diminishing associated pain are provided. The formulation includes glucosamine, conjugated linoleic acid and ascorbic acid. Methods of treatment are also provided. The compositions and methods can be provided as an over-the-counter drug, a nutritional supplement, a prescription medication or component thereof, or a functional or medical food or component thereof.

BACKGROUND OF THE INVENTION

The present invention relates generally to methods of treatment andproducts for treating disorders. More specifically, the presentinvention relates to methods and compositions for preventing, treatingor providing relief from inflammation of the joints, osteoarthritis, andother degenerative joint diseases, or from pain associated with theseconditions.

Inflammation of the joint is a common disorder. One result of suchchronic inflammation, osteoarthritis (osteoarthrosis), is a degenerativeprocess that is a major cause of invalidism in the adult population.Osteoarthritis is the most common form of all articular disorders, andfirst appears asymptomatically in the second or third decades andbecomes almost universal by age 70. Almost all persons by the age of 40have some pathological changes in weight bearing joints, althoughrelatively few people are symptomatic. See Merck Manual, 16 Edition,page 1339.

The etiology of osteoarthritis is unknown. It appears to be the resultof a complex system of interacting mechanical, biological, biochemical,and enzymatic feedback loops. When one or more of these systems fails,the clinical events follow. Many mechanisms can initiate the cellularand tissue events that constitute a final common pathway. Suchmechanisms include: congenital joint abnormalities; genetic defects;infectious, metabolic, endocrine, and neuropathic diseases; virtuallyany disease process that alters the normal structure and function ofhyaline cartilage; and acute or chronic trauma to the hyaline cartilageor tissue surrounding same. Merck Manual, id.

Analgesics and anti-inflammatory agents are used to attempt to managethis disorder. However, they do not stop or slow down the underlyingdegenerative process, they only function to relieve the pain. Althoughsuch nonsteroidal anti-inflammatory drugs have classically been used toalleviate pain and enhance joint movement associated with osteoarthritisand rheumatoid arthritis, their use is unfortunately associated withaccelerated cartilage degeneration. The cartilage degeneration is due tothe pathological effects of IL-1, EL-6, TNF, and PGF2, mediators of theacute phase response. The combined effects of these catabolic agentsupset the delicate homeostatic balance between synthesis, repair, anddegradation of cartilage.

There is a need for improved compositions and methods for treatingdegenerative joint disease such as osteoarthritis.

SUMMARY OF THE INVENTION

Pursuant to the present invention, methods and compositions forpreventing and treating degenerative joint diseases includingosteoarthritis as well as inflammation of the joints, as well asassociated pain are provided. The formulation includes glucosamine,conjugated linoleic acid, and ascorbic acid. Methods of treatment arealso provided. The compositions and methods can be provided as anover-the-counter drug, a nutritional supplement, or a prescriptionmedication or component thereof, or as a component of functional ormedical foods.

To this end the present invention provides a method for preventing ortreating degenerative joint disease comprising the step of administeringa therapeutically effective amount of a composition comprisingconjugated linoleic acid, glucosamine, and ascorbic acid.

In an embodiment, approximately 0.5 to about 10.0 grams per day ofconjugated linoleic acid are administered.

In an embodiment, approximately 500 mg to about 2500 mg per day ofglucosamine is administered. Preferably 1500 mg to 2500 mg per day.

In an embodiment, approximately 50 mg to about 500 mg per day ofascorbic acid is administered. Preferably 100 mg to 400 mg per day.

In an embodiment, the conjugated linoleic acid is either a pure isomerof octadecadienoic acid, or a mixture of octadecadienoic acid isomersselected from the group consisting of: cis-8, cis-10; cis-8, trans-10;trans-8, cis 10; trans-8, trans-10; cis-9, cis-11; cis-9, trans-11;trans-9, cis-11; trans-9, trans-11; cis-10, cis-12; cis-9, trans-12;trans-9, cis-12; trans-10, trans-12; cis-11, cis-13; cis-11, trans-13;trans-11, cis-13; trans-11, trans-13 octadecadienoic acid; metabolitesthereof, including but not limited to 18:3 cis-6, cis-9, trans-11; 18:3cis-6, trans-10, cis-12; 18:3 cis-8, trans-12, cis-14; 20:3 cis-8,cis-11, trans-13; 20:4 cis-5, cis-8, cis-11, trans-13; 20:4 cis-5,cis-8, trans-12, cis-14; as well as precursors or derivatives thereof.

In an embodiment, the composition includes a flavor.

In an embodiment, the composition includes an artificial sweetener.

In an embodiment, the composition is in pill form.

In an embodiment, the degenerative joint disease is osteoarthritis. Inan embodiment, the degenerative joint disease is rheumatoid arthritis,or associated disorders.

In a further embodiment of the present invention, a composition isprovided comprising a therapeutically effective amount of conjugatedlinoleic acid, glucosamine, and ascorbic acid.

In an embodiment, the composition comprises approximately 14% to about87% by weight conjugated linoleic acid.

In an embodiment, the composition comprises approximately 12% to about82% by weight glucosamine.

In an embodiment, the composition comprises approximately 0.1% to about20% by weight ascorbic acid.

In yet another embodiment of the present invention, a method of treatinginflammation of the joints is provided comprising the step ofadministering a therapeutically effective amount of a compositioncomprising conjugated linoleic acid, glucosamine, and ascorbic acid.

It is an advantage of the present invention to provide a composition fortreating inflammation of the joints.

Another advantage of the present invention is to provide a compositionand method for treating osteoarthritis and other degenerative jointdiseases.

Still further, an advantage of the present invention is to provide aproduct that can reduce the damaging degenerative process involved injoint disease.

Further, an advantage of the present invention is to provide a productand method that can reverse the damaging degenerative process involvedin joint disease.

Moreover, an advantage of the present invention is to provide acomposition and method for reducing the debilitating pain associatedwith joint disease.

Furthermore, an advantage of the present invention is to provide acomposition and method for increasing mobility in patients withdegenerative joint disease.

A further advantage of the present invention is to provide a compositionand method for alleviating the chronic catabolic stress responseassociated with degenerative joint disease.

Still, an advantage of the present invention is to provide a compositionand method for reducing inflammatory response associated with jointdiscomfort.

Additionally, an advantage of the present invention is to provide acomposition and method for enhancing cartilage synthesis and/orpreventing or minimizing cartilage degradation, thus promoting cartilagerepair mechanisms.

Additional features and advantages of the present invention will bedescribed in and apparent from the detailed description of the presentlypreferred embodiments.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

Pursuant to the present invention, methods and compositions for treatingdegenerative joint diseases including osteoarthritis as well asinflammation of the joints are provided. The formulation includesglucosamine, conjugated linoleic acid, and ascorbic acid. Methods oftreatment are also provided. The composition and method can be providedas an over-the-counter drug, a nutritional supplement, or a prescriptionmedication.

Glucosamine is a component of all human tissue and is found inespecially high concentrations in the cartilage. Chemically anaminomonosaccharide, glucosamine provides the building blocks for theO-linked and N-linked glycosaminoglycans comprising the matrix of theconnective tissues in the body. The sulfate form is readily absorbedfrom the small intestine—over 90%. Of the absorbed glucosamine, 25% willbe excreted in the urine, 65% excreted as exhaled carbon dioxide, and10% remaining in the tissues. Once it is taken up into the chondrocytesof cartilage, glucosamine is incorporated into proteoglycans. There havebeen no reports of significant drug interactions of glucosamine withantibiotics or antidepressants.

Vitamin C is an essential vitamin with an RDI of 60 mg per day. Thedeficiency of this vitamin is associated with poor wound healing, mostlikely due to poor collagen synthesis. This water-soluble vitamin is notusually stored, thus, there is little evidence of toxicity.

Current evidence suggests that pro-inflammatory cytokines areresponsible for the catabolic process occurring in the pathologicaltissues. In addition to other cataboic mediators, these pro-inflammatorymediators, particularly interleukins (IL-1, EL-6), and tumor necrosisfactor (TNF)-α, are major catabolic compounds involved in thedestruction of joint tissues. In the inflammatory response ofosteoarthritic articular cells, the changes in cyclooxygenase-2 (COX-2)expression and/or activity seems one of the major determinants forprostaglandin (PGE₂) production. Chondrocytes are highly sensitive toIL-1 and it appears this cytokine inhibits repair and regeneration ofextracellular matrix and increases catabolic activity of the mate.Speculation is that immunological mediators (humoral and locallyproduced) play a primary role in skeletal muscle remodeling and perhapscartilage remodeling as well. Thus, it appears necessary to modify thiscatabolic event to retard and/or reverse the breakdown of cartilage.

Conjugated linoleic acid refers to a group of di- and tri-enoicderivatives of linoleic acid that occur naturally in milk and meat ofruminating animals. It can be synthesized in the laboratory and isavailable commercially as a dietary supplement and has been shown to benontoxic.

Pursuant to the present invention, conjugated linoleic acid can beconjugated linoleic acid such as that set forth in U.S. Pat. No.5,986,116 the disclosure of which is incorporated herein by reference.

Conjugated linoleic acid appears to modulate the immune system underconditions where COX-2 enzyme is induced by suppressing PGE-2production. The mechanism for the observed anti-inflammatory effects ofconjugated linoleic acid in various animal models has been associatedwith reduced arachidonic acid, a precursor for PGE, accumulation in cellmembranes. Any effect conjugated linoleic acid has on the synthesis ofeicosanoids should correlate with the uptake of conjugated linoleic acidinto neutral phospholipids by cells. Conjugated linoleic acid can bereadily incorporated in a dose-dependent manner into the tissues ofanimals consuming diets containing conjugated linoleic acid and aconcomitant reduction of arachidonic acid.

Human articular cartilage is highly specialized tissue, composed ofchondrocytes embedded in an extracellular matrix. The matrix containsfibrillar components consisting mainly of collagen proteins, andnon-fibrillar components, made up of proteoglycans, hyaluronic acid andwater. Proteoglycan subunits consist of glycosaminoglycans (chondroitinand keratin sulfates) surrounding a protein core. Cartilage metabolisminvolves processes of synthesis, repair and degradation, which areongoing and mediated by chondrocytes. When the balance among theseprocesses is upset as in osteoarthritis and rheumatoid arthritis,cartilage damage results. The breakdown of the cartilage matrix isbelieved to be due to locally produced IL-1 from inflammatory cellsincreasing catabolic activity in adjacent chondrocytes. Thus, CLA mayinhibit catabolic response while oral glucosamine stimulates themanufacture of substances necessary for proper joint function andstimulate joint repair.

Orally administered glucosamine sulfate is selectively taken up by thearticular cartilage and stimulates the manufacture of glycosaminoglycan,a key structural component of cartilage. It also promotes theincorporation of sulfur into cartilage. Ascorbic acid acts as areductive cofactor for post-translational hydroxylation of peptide boundproline and lysine residues during formation of collagen. Thesehydroxylated amino acids allow cross-linking which stabilizes the triplehelical structure of tropocollagen, an essential subunit of procollagen.Ascorbic acid may be involved in gene regulation of collagen synthesisand mRNA processing. In addition, ascorbic acid influences cellularprocollagen secretion and biosynthesis of other connective tissuecomponents such as elan proteoglycans and bone matrix. Ascorbic acid isalso involved with various immune-related functions such as neutrophilchemotaxis, lymphocyte proliferation, antimicrobial and natural killercell activities and may also modulate prostacyclin, prostaglandins, andB- and T-cell cyclic nucleotides. The mechanisms for these effects arenot clearly resolved, nor the absolute amount of ascorbic acid needed toassist in these areas. Because the normal dietary intake of ascorbicacid in humans is often less than 60 mg set as the recommended dailyintake (RDI), it appears prudent to add this important cofactor as anactive ingredient in this unique formula. Inclusion of this essentialvitamin may assist in promoting collagen formation and wound healing.

By way of example and not limitation, examples of the present inventionwill now be given.

Proposed Formulations:

Preferably, the product will comprise as active ingredients:

-   -   approximately 14% to about 87% by weight conjugated linoleic        acid;    -   approximately 12% to about 82% by weight glucosamine SO₄; and    -   approximately 0.5% to about 20% by weight ascorbic acid.

In a preferred embodiment, the product will comprise as activeingredients:

conjugated linoleic acid 45% glucosamine SO₄ 45% ascorbic acid 10%

By way of example, it is envisioned that a dose of the product willcomprise two tablets of conjugated linoleic acid/clucosaminesulfate/ascorbic acid. Each dose (two tablets) will contain:

conjugated linoleic acid powder 500 mg; glucosamine SO₄ 500 mg; andascorbic acid 100 mg.

The tablets may include the following excipients and flavorings:magnesium stearate, silicone dioxide, croscarmelose sodium, sterricacid, microcrystalline cellulose, calcium phosphate, aqueous base filmcoat.

By way of example and not limitation, contemplative examples of thepresent invention will now be given.

CONTEMPLATIVE EXAMPLE NO. 1

To treat osteoarthritis, a daily administration of formulation will begiven in an amount to provide:

20 mg/kg/day conjugated linoleic acid to 100 mg/kg/day conjugatedlinoleic acid, 1500 mg/day glucosamine to 2500 mg/day glucosamine, and100 mg/day ascorbic acid to 400 mg/day ascorbic acid.

CONTEMPLATIVE EXAMPLE NO. 2

To treat rheumatoid arthritis, a daily administration of formulationwill be given in an amount to provide:

20 mg/kg/day conjugated linoleic acid to 100 mg/kg/day conjugatedlinoleic acid, 1500 mg/day glucosamine to 2500 mg/day glucosamine, and100 mg/day ascorbic acid to 400 mg/day ascorbic acid.

CONTEMPLATIVE EXAMPLE NO. 3

To treat joint discomfort and pain, a daily administration offormulation will be given in an amount to provide:

20 mg/kg/day conjugated linoleic acid to 60 mg/kg/day conjugatedlinoleic acid, 1500 mg/day glucosamine to 2500 mg/day glucosamine, and100 mg/day ascorbic acid to 400 mg/day ascorbic acid.

CONTEMPLATIVE EXAMPLE NO. 4 Prophylactic (Maintain Joint Health)

To maintain joint health a daily administration of formulation will begiven in an amount to provide:

20 mg/kg/day conjugated linoleic acid to 60 mg/kg/day conjugatedlinoleic acid, 1500 mg/day glucosamine to 2500 mg/day glucosamine, and100 mg/day ascorbic acid to 400 mg/day ascorbic acid.

It should be understood that various changes and modifications to thepresently preferred embodiments described herein will be apparent tothose skilled in the art. Such changes and modifications can be madewithout departing from the spirit and scope of the present invention andwithout diminishing its intended advantages. It is therefore intendedthat such changes and modifications be covered by the appended claims.

1. A method for treating arthritis, osteoarthritis, or joint paincomprising the step of administering to an animal a therapeuticallyeffective amount of a composition comprising conjugated linoleic acid,glucosamine, and ascorbic acid.
 2. The method of claim 1 whereinapproximately 0.5 to about 10 grams per day of conjugated linoleic acidare administered.
 3. The method of claim 1 wherein approximately 1500 mgto about 2500 mg per day of glucosamine is administered.
 4. The methodof claim 1 wherein approximately 100 mg to about 400 mg per day ofascorbic acid is administered.
 5. The method of claim 1 wherein theconjugated linoleic acid is selected from the group consisting of: apure isomer of octadecadienoic acid; mixtures of octadecadienoic acidisomers: cis-8, cis-10; cis-8, trans-10; trans-8, cis-10; trans-8,trans-10; cis-9, cis-1; cis-9, trans-11; trans-9, cis-11; trans-9,trans-11; cis-16, cis-12; cis-9 trans-12; trans-9, cis-12;trans-10-trans-12; cis-11, cis-13; cis-11, trans-13; trans-11, cis-13;octadecadienoic acid.
 6. The method of claim 1 wherein the compositionincludes a flavor.
 7. The method of claim 1 wherein the compositionincludes an artificial sweetener.
 8. The method of claim 1 wherein thecomposition is in pill form.
 9. The method of claim 1 wherein thedegenerative joint disease is osteoarthritis.
 10. A compositioncomprising a therapeutically effective amount of conjugated linoleicacid, glucosamine, and ascorbic acid.
 11. The composition of claim 10wherein approximately 14% to about 87% by weight of the composition isconjugated linoleic acid.
 12. The composition of claim 10 whereinapproximately 12% to about 82% by weight of the composition isglucosamine.
 13. The composition of claim 10 wherein approximately 0.5%to about 20% by weight of the composition is ascorbic acid.
 14. Thecomposition of claim 10 wherein the conjugated linoleic acid is selectedfrom the group consisting of: a pure isomer of octadecadienoic acid;mixtures of octadecadienoic acid isomers: cis-8, cis-10; cis-8,trans-10; trans-8, cis-10; trans-8, trans-10; cis-9, cis-11; cis-9,trans-11; trans-9, cis-11; trans-9, trans-11; cis-10, cis-12; cis-9trans-12; trans-9, cis-12; trans-10-trans-12; cis-1, cis-13; cis-11,trans-13; trans-11, cis-13; trans-11, trans-13 octadecadienoic acid. 15.The composition of claim 10 wherein the composition includes a flavor.16. The composition of claim 10 wherein the composition includes anartificial sweetener.
 17. The composition of claim 10 wherein thecomposition is in pill form.
 18. A method of treating inflammation ofthe joints comprising the step of administering to an animal atherapeutically effective amount of a composition comprising conjugatedlinoleic acid, glucosamine, and ascorbic acid.
 19. The method of claim18 wherein approximately 0.5 to about 10 grams per day of conjugatedlinoleic acid are administered.
 20. The method of claim 18 whereinapproximately 1500 mg to about 2500 mg per day of glucosamine isadministered.
 21. The method of claim 18 wherein approximately 100 mg toabout 400 mg per day of ascorbic acid is administered.
 22. The method ofclaim 18 wherein the conjugated linoleic acid is selected from the groupconsisting of: a pure isomer of octadecadienoic acid; mixtures ofoctadecadienoic acid isomers: cis-8, cis-10; cis-8, trans-10; trans-8,cis-10; trans-8, trans-10; cis-9, cis-11; cis-9, trans-11; trans-9,cis-11; trans-9, trans-11; cis-10, cis-12; cis-9 trans-12; trans-9,cis-12; trans-10-trans-12; cis-11, cis-13; cis-11, trans-13; trans-11,cis-13; trans-11, trans-13 octadecadienoic acid.
 23. The method of claim18 wherein the composition includes a flavor.
 24. The method of claim 18wherein the composition includes an artificial sweetener.
 25. The methodof claim 18 wherein the composition is in pill form.